8-oxa-3-azabi cyclo(3.2.1)octane compounds

ABSTRACT

Disclosed are compounds, having the following general formula, which are useful as analgesics in living animals. (a) WHEREIN R is a radical selected from the group consisting of aralkyl, aryl, aminoalkyl, arylalkanoyl, heteroaroyl, alkoxy substituted aroyl, alkenyl (C2 to C4), halogen substituted araklyl, guanadinoalkyl, halogen substituted aroyl, alkyl substituted aroyl, halogen substituted arylalkanoyl, hexahydrobenzoyl, arylalkenoyl, o- and p-alkyl substituted phenylalkanoyl, alkyl substituted naphthylalkanoyl, alkanoyl (C3 to C20), haloalkyl substituted aroyl, alkoxy substituted aralkyl, heteroaralkyl, anilinocarbonyl, adamantanecarbonyl, arylsulfonyl, carboxyl substituted aroyl, hydroxyl substituted aroyl, alkanoyloxy substituted aroyl, arylglyoxylyl, alicyclic, arylene dicarbonyl-8-oxa-3-azabicyclo(3.2.1) octane, alkylene-8-oxa-3azabicyclo (3.2.1)octane, alkylene dicarbonyl-8-oxa-3azabicyclo(3.2.1)octane, and the pharmacologically acceptable acid addition salts thereof.

nited States Paten [1 1 Miller 8-0XA-3-AZABICYCLO(3.2.1)OCTANE COMPOUNDS [75] Inventor: Alfred D. Miller, Wilmington, Del.

[73] Assignee: ICI United States lnc., Wilmington,

Del.

[22] Filed: June 14, 19 73 [21] Appl. No.: 370,011

[52] US. Cl 260/240 D, 260/244 R, 424/248 [51] Int. Cl C07d 87/28 [58] Field of Search.- 260/240, 244

[56] References Cited v OTHER PUBLICATIONS Cope et al'., I, J. 'Am. Chem. Soc., vol. 77, pp. 393-396 (1955). Cope et al., II, J. Am. Chem. Soc., vol. 81, pp. 4577-4583 (1959).

Newth et al., J. Chem. Soc., pp. 155-158 (1948).

Primary Examiner-Harry I. Moatz Attorney, Agent, or Firm -ICI United States Inc.

57 i ABSTRACT Disclosed are compounds, having the following gen- Dec. 24, 1974 era] formula, which are useful usunalgesics in living animals. (a)

I I (a) Q N-R aroyl, alkanoyloxy substituted aroyl, arylglyoxylyl, ali

cyclic, arylene dicarbonyl-8-oxa-3-azabicyclo(3.2.1)

octane, alkylene-8-oxa-3-azabicyclo (3.2.l)octane, alkylene .dicarbonyl-8-oxa-3-azabicyclo(3.2. 1 )octane, and the pharmacologically acceptable acid addition salts thereof.

31 Claims, No Drawings 8-OXA-3-AZABICYCLO(3.2.1)OCTANE COMPOUNDS This invention relates to 8-o xa-3-azabicyclo(3.2.l)

octane compounds and to their methods of preparation and use.

The-physiologically active compounds of the present invention are illustrated by the following general formula (a) N-R wherein R is a radical selected from the group consisting ofaralkyl, aryl, aminoall'tyl, arylalkanoyl, heteroar-' oyl, alkoxy substituted aroyl, alkenyl (C to C halogen substituted aralkyl, guanadinoalkyl, halogen substi- (a) include the following within their scope. The term aralkyl includes, for example, benzyl, phenethyl, amethylphenethyl, 0-, m-, and p-methylbenzyl, naphthylethyl, and phenylpropyl, wherein the alkyl portion of said radical is straight or branch chained and contains from I to 10 carbon atoms and the aryl portion is phenyl or naphthyl. Alkylene-8-oxa-3- oxa-3-azabicyclo(3.2.l )octane includes such radicals wherein the alkylene portion thereof contains from 1 to 10 carbon atoms. The term aryl by itself or in combination with other radicals is used herein to denote radicals, such as phenyl and naphthyl. Aminoalkyl represents an amine group substituted with l to 3 alkyl groups havingfrom l to 10 carbon atoms. Alkanoyl as used herein by itself or in combination with other radicals includes such radicals having from 3 to-20 carbon atoms, for example, isobutyrol, propionyl, caproyl, stearoyl, and heptanoyl. Alkanoyl" when used herein in combination with other radicals includes such radicals having from 2 to 20 carbon atoms. Therefore, the term arylalkanoy|" includes radicals, such as, for example, phenylacetyl, phenylcaproyl, phenylstearoyl, and naphthylheptanoyl. The radical heteroaroyF ineludes, for example, nicotinoyl, thenoyl,,and quinoxaloyl. When the term alkyl" is used herein by itself or in combination with other radicals, it'denotes both straight and branched chain alkyl radicals containing from I to 10 carbon atoms. For example,the alkyl portion of an alkyl substituted aroyl radical can contain from I to 10 carbon atoms and the aroyl radical can be substituted with at least I and no more than 5 such alkyl groups, preferably 1 to 3. Further, for example, the alkyl portion of a guanadinoalkyl radical includes .azabicyclo(3.2.l) octane and alkylene dicarbonyl-8- alkyl radicals containing from 1 to 10 carbon atoms. Aroyl as used herein by itselfor in combination with other radicals includes unsubstituted radicals, for example, naphthoyl and benzoyl. Haloalkyl substituted aroyl radicals include aroyl radicals substituted with at least 1 and no more than 3 haloalkyl radicals each of which contains from 1 to 10 carbon atoms and at least 1 and no more than 6 halogen atoms. When halogen is referred to in relation to any of the radicals represented by R,'all halogens are intended and thus fluorine, chlorine, iodine, and bromine are included; however, fluorine, chlorine, and bromine are preferred. Alkoxy substituted aroyl as used herein includes aroyl radicals substituted with at least 1 and no more than 3 alkoxy groups which each contains from I to 10 carbon atoms and includes radicals, such as methoxybenzoyl, pentoxybenzoyl, and 3,5-dibutoxynaphthoyl. The radical arylsulfonyl" includes, for example, benzenesulfonyl and naphthalenesulfonyl. For example. alicyclic" includes cycloalkyl radicals having from 3 to 8 ring carbon atoms, such as cyclopropyl, cyclopen tyl, cyclohexyl, and cycloheptyl. By alkenyl" is included, for example, straight and branched chain radicals containing from 2 to 4 carbon atoms. The term arylalkenoyl as used herein includes radicals, such as cinnamoyl and other such radicals, wherein the alkenoyl portion of the radical contains from 3 to 10 carbon atoms. The term alkanoyloxy substituted aroyl" as used herein includes radicals, such as acetoxybenzoyl and acetoxynaphthoyl, wherein the alkanoyloxy portion of the radicals contains from 2 to 10 carbon atoms and the aroyl radical is substituted with at least 1 and no more than 3 alkanoyloxy radicals. The terms halogen substituted aralkyl," halogen substituted aroyl," and halogen substituted arylalkanoyl are used to indicate such radicals which are substituted with at least 1 and no more than 5 halogen atoms, preferably 1 to 3 halogen atoms. Heteroaralakyl includes, for example, radicals, such as thienylethyl, thienylhexyl, a-methylthienylethyl, and pyridylbutyl. oand p-Alkyl substituted phenylalkanoyl includes radicals which are substituted with l to 3 (C, to C alkyl radicals. Alkyl substituted naphthylalkanoyl" radicals include 'such radicals substituted on the aromatic ring with up to 5 (C, to C alkyl radicals. Alkoxy substituted aralkyl" includes aralkyl radicals substituted with at least 1 and no more than 5 alkoxy groups (C to C preferably 1 to 3 such alkoxy groups. Carboxyl substituted aroyl" and hydroxyl substituted aroyl" includes aroyl radicals suitably substituted with at least 1 and no more than 5 carboxyl or hydroxyl groups, as the case may, preferably substituted with l to 3 ofsuch groups.

Pharmacological studies indicate that the 8-oxa-3- azabicyclo(3.2.l )octane compounds of the present in- It has also been found that 8-oxa-3-' azabicyclo(3.2.l )octane, 3-benzoyl-8-oxa-3- azabicyclo(3.2.l )octane, 3-alkyl (C, to C,,)-8-oxa-3- azabicyclo(3.2.l )octane, and 3-acetyl-8-oxa-3- azabicyclo(3.2.l )octane are effective as analgesics when administered to living animals. Further, the pharmacologically acceptable'acid addition salts of these compounds have also been found to have analgesic activity.

In a preferred subclass of the present invention, R in formula (a) above is selected from the group consisting of: phenyl; aminoalkyl (C, to C,,) where the amino group is primary, secondary, or tertiary;-phenylacetyl; quinoxaloyl; mono-, di-, or tri-alkoxy (C, to C substituted benzoyl; phenylalkyl where the alkyl constituent thereof contains from 1 to 4 carbon atoms such as benzyl, phenylpropyl, and phenethyl; alkenyl (C and C mono-, di-, or tri-halogen substituted phenylalkyl where the alkyl group contains from 1 to 4 carbon atoms and the halogen is substituted on the phenyl ring; guanadinoalkyl (C, to C mono-, di-, or tri-halogen substituted benzoyl; mono-, di, or tri-alkyl (C, to C substituted benzoyl; mono-, di-, or tri-halogen substituted phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms and the halogen is on the phenyl ring; hexahydrobenzoyl; phenylalkenoyl wherein the alkenoyl group is a lower alkenoyl containing from 3 to 5 carbon atoms; phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms; and p-alkyl (C, to C substituted phenylalkanoyl where the alkanoyl group contains 2 to 4 carbon atoms and the alkyl group is substituted on the phenyl ring; alkyl (C, to C substituted naphthylalkanoyl where the alkanoyl group contains 2 to 4 carbon atoms and the alkyl group or groups, preferably 1 to 3 alkyl groups, are attached to the naphthyl ring; alkanoyl (C to C,,,); haloalkyl (C, to C mono-, di-, or tri-substituted benzoyl wherein the haloalkyl group contains from 1 to 5 halogen atoms; mono-, di-, or tri-alkoxy (C, to C substituted phenylalkyl wherein the alkyl group contains 1 to 4 carbon atoms and the alkoxy is substituted on the phenyl ring; thienylalkyl wherein the alkyl group contains from 1 to 4 carbon atoms; anilinocarbonyl; adamantanecarbonyl; phenylsulfonyl; monoor dicarboxyl substituted benzoyl; monoor di-hydroxyl substituted benzoyl; nicotinoyl; mono-or dialkanoyloxy (C, to C substituted benzoyl; thenoyl; phenylglyoxylyl; cycloalkyl (C to C terephtholoyl-S- oxa-3-azabicyclo(3.2.l )octane; alkylene (C, to C,,)-8- oxa-3-azabicyclo(3.2.l )octane, and alkylene (C, to C,,) dicarbonyl-8-oxa-3-azabicyclo(3.2. l )octane. When halogen is referred to in this subclass, all halogens are intended; however, fluorine, chlorine, and bromine are preferred. ln this preferred subclass, the above radicals, representing R in formula (a) above, can be substituted suitably in any of the ortho, meta, or para positions on the ring or any combination thereof unless otherwise directly indicated. For example, ring structures of the present preferred species of substituent R in formula (a) may be substituted in two ortho positions or two meta positions and/or the para position, or one ortho and one para position or any desired position combinations thereof.

The terms lower alkyl," lower alkoxy," lower haloalkyl," lower alkanoyl," and .lower alkanoyloxy can be used to describe such radicals as referred to above in the preceding paragraph when they contain up to 4 carbon atoms.

In another preferred subclass of the presentinvention R in formula (a) above is selected from the group consisting of benzyl, phenyl, aminohexyl, phenylacetyl, quinoxaloyl m-methoxybenzoyl, a-methylphenethyl, aminoethyl, propenyl, a-methyl p-chlorophenethyl, dimethylaminopropyl, phenethyl, 2-guanadinoethyl, p-chlorobenzoyl, p-toluoyl, m-chlorobenzoyl, ochlorobenzoyl, o-toluoyl, m-chlorophenylacetyl, pchlorophenylacetyl, m-toluoyl, ethylene-8-oXa-3- azabicyclo(3.2.l )octane,-- B-methylphenethyl. B,B-dimethylphenethyl, p-chlorophenethyl, hexahydrobenzoyl, o-chlorophenylacetyl, cinnamoyl, phenethylcarbonyl, o-methylphenylacetyl, heptanoyl, m-trifluoromethylbenzoyl, o-methoxyphenethyl, a-methylthienylethyl, anilinocarbonyl, adamantanecarbonyl, phenylsulfonyl, o-carboxybenzoyl, stearoyl, propanoyl, o-hydroxybenzoyl, nicotinoyl,o-acetoxybenzoyl, thenoyl, phenylglyoxylyl, cyclohexyl, 3,4-dimethoxyphenethyl, hexamethylene-8-oxa-3- azabicyclo(3.2. l )octane, adip'yl-8-oxa-3- azabicyclo(3.2.l) octane, terephtholoyl-8-oxa-3- azabicyclo(3.2.l)octane, and the pharmacologically acceptable acid addition salts thereof.

Among the novel compounds of the present invention are, for example: 3-phenylacetyl-8-oxa-3- azabicyclo(3.2. l )octane; 3-(p-chlorobenzoyl)-8-oxa- 3-azabicyclo(3.2. l )octane; 3-heptanoyl-8-oxa-3- azabicyclo(3.2.l )octane; 3-nicotinoyl-8-oxa-3- azabicyclo (3.2.l)octane; 3(m-chlorobenzoyl)-8-oxa- 3-azabicyclo(3.2. l octane; 3(o-chlorobenzoyl)-8-oxa- 3-azabicyclo(3.2.l)octane; 3-(p-toluoyl)-8-oxa-3- azabicyclo(3.2.l )octane; 3-(m-chlorophenylacetyl )-8- oxa-3-azabicyclo( 3.2. l )octane; 3-(0- chlorophenylacetyl)-8-oxa-3-azabicyclo(3.2.l )octane; 3-cinnamoyl-.8-oxa-3-azabicyc|o(3.2. l )octane; 3-(ptolylacetyl )-8-oxa-3-azabicyclo( 3.2. l )octane; 3-( pchlorophenylacetyl)-8-oxa-3-azabicyclo(3.2.l )octane; 3-(o-tolylacetyl)-8-oxa-3-azabicyclo(3.2.l )octane; 3-

-(Z-quinoxaloyl)-8-oxa-3-azabicyclo(3.2.l) octane; 3-

azabicyclo( 3.2.l )octane; 3-(a-thenoyl)-8-oxa-3- azabicyclo( 3.2.1 )octane; 3-heptanoyl-8-oxa-3- azabicyclo(3.2.l) octane; 3-hydrocinnamoyl-8-oxa-3- azabicyclo(3.2.l )octane; 3-(o-t0luoyl)-8-oxa-3- azabicyclo)3.2.l )octane; 3-(m-toluoyl)-8-oxa-3- azabicyclo(3.2.l )octane; 3-hexahydrobenzoyl-8-oxa- 3-azabicyclo(-3.2. l )octane; 3-(m-methoxybenzoyl )-8 oxa-3-azabicyclo (3.2.l)octane; 3-stearoyl-8-oxa-3- azabicyclo(3.2.l )octane; 3-propionyl-8-oxa-3- azabicyclo(3.2. l )octane; 3-nicotinoyl-8-oxa-3- azabicyclo(3.2.l)octane; 3-(acetylsalicyloyl)-8-oxa-3- azabicyclo( 3.2. l )octane; 3-(o-carboxybenzoyl 8- oxa-3-azabicyclo (3.2. l )octane; 3-( ladamantanecarbonyl )-8-oxa-3-azabicyclo( 3.2.l octane; 3-(phenylglyoxylyl)-8-oxa-3- azabicyclo(3.2l )octane; 3-(o-hydroxybenzoyl)-8-oxa- 3-azabicyclo(3.2.l )octane; 3-benzenesulfonyl-8-oxa-3- azabicyclo(3.2.l)octane; 3-(N-phenylcarbamoyl)-8- oxa-3-azabicyclo( 3.2.l )octane; 3-allyl-8-oxa-3- azabicyclo (3.2.l)octane hydrochloride; 3-cyclohexyl- 8-oxa-3-azabicyclo (3.2.l)octane hydrochloride; 3- phenyl-8-oxa-3-azabicyclo( 3.2.l )octane; 3-phenyl-8- oxa-3-azabicyclo)(3.2.l)octane hydrochloride; 3-(pchlorophenethyl)-8-oxa-3-azabicyclo(3.2.l )octane hydrochloride; 3-(a-methylphenethyl )-8-oxa-3- azabicyclo(3.2.l )octane hydrochloride; 3-( amethylphenethyl)-8-oxa-3-azabicyclo(3.2.l )octane;

3-(3,4-dimethoxyphenethyl)-8-oxa-3- azabicyclo(3.2.1)octane; 3-(3,4-dimethoxyphenethyl)- 8-oxa-3-azabicyclo(3.2.l)octane hydrochloride; 3* benzyl-8-oxa-3-azabicyclo(3.2.1)octane hydrochloride; 3-phenethy1-8-oxa-3-azabicyclo(3.2.1)octane hydrochloride; 3-(p-chlorophenethyl)-8-oxa3- azabicyclo(3.2.1)octane hyrochloride; 3-(pmethoxyphenethyl)-8-oxa-3-azabicyc1o(3.2.1)octane hydrochloride; 3-(ma-diinethylphenethyl)-8-oxa-3- azabicyclo(3.2.1)octane hydrochloride; 3-(B- methylphenethyl)-8-oxa-3-azabicyclo(3.2.1)octane hydrochloride; 3- (a-methyl-p-chlorophenethyl)-8-oxa- 3-azabicyclo(3.2. l )octane hydrochloride; 3-[1-(2- thienyl)isopropyl]-8-oxa-3-azabicyclo(3.2.1)octane hydrochloride; 3-(3dimethylaminopropyl)-8-oxa-3- azabicyclo (3.2.1 )octane dihydrochloride; 3-(2- aminoethyl)-8-oxa-3 azabicyclo(3.2. 1 )octane dihydrochloride; 3,3-ethylene -bis[8-oxa-3- azabicyclo(3.2.l )octane]; 3-(6-aminohexamethylene)- 8-oxa-3-azabicyclo(3.2.l )octane; 3,3'hexamethylenebis[8-oxa-3-azabicyclo(3.2.1)octane]; 3-(2- guanadinoethyl)-8-oxa-2-azabicyclo(3.2.1 )octane hydrosulfate monohydrate; and the pharmacologically acceptable acid addition salts of such basic compounds.

The immediate precursor for making most of the novel compounds of the present invention is 8-oxa-3- azabicyclo(3.2.l)octane. This compound can be readily prepared by a two-step process as illustrated in the following Eamples 1 and 2, starting with cis-2,5-bis- (hydroxymethyl)tetrahydrofuran. The compound cis- 2,5 -bis-(hydroxymethyl)tetrahydrofuran is prepared by the method disclosed in US. Pat. No. 3,040,062 or by methods disclosed by Newth and Wiggins, Research, London, Vol. 3, Supplement 3-1, pages 50-51. (1950);

'Turner et a|., Analytical Chemistry, 26, 898-901 1954); or Cope and Baxter, Journal American Chemical Society, 77, 393-396 (1955). Using cis-2,5-bis- (hydroxymethyl) tetrahydrofuran as the starting material, the ditosylate thereof is prepared by reaction with p-toluenesulfonyl chloride in pyridine. The resulting compound, cis-2,5-bis-(tosyloxymethyl) tetrahydrofuran, represented hereinafter by formula (11), can then be reacted with an ammonia-alcohol solution under pressure, as illustrated in Example 2, to form 8-oxa-3- azabicyclo(3.2.1)octane, represented hereinafter by formula (111). All of the novel compounds of the pres- EX E cis-2,5-Bis-(Tosy1oxymethyl)Tetrahydrofuran CH2OH l o 2 ECH C H OSOCl LCH2OH To a three-neck flash equipped with a thermometer, reflux condenser, mechanical stirrer, and dropping funnel a solution of 924 grams (7 moles) of cis-2,5-bis- (hydroxymethyl) tetrahydrofuran, represented by formula (I), in 900 ml of pyridine was placed and cooled at 5C. A solution of 2669 grams (14 moles) of ptoluenesulfonyl chloride in 4 liters of pyridine was added slowly through the dropping funnel. The temperature during the addition was kept below 1015C. After the addition of p-toluenesulfonyl chloride, the reaction mixture was stirred for 2 hours and then let stand at room temperature overnight. The reaction mixture was poured over ice-water and the product precipitated. The ditosylate, represented by formula (11), was filtered off and washed several times with water and dried. The product obtained had a melting point of l25126.5 C.

EXAMPLE 2 8-Oxa-3 -Azabicyclo(3.2.1 )Octane ent invention, as well as those utilized in the claimed method of treatment, are cis isomers. Compound (11]), in turn, can be converted to the hydrochloride salt as shown in Example 3, which as indicated can also be used as aprecursor in making other compounds of the present invention. The acetate salt of 8-oxa-3- azabicyclo(3.2.1 )octane can be prepared as illustrated in Example 4. Example 4 illustrates another method of preparing 8-oxa-3-azabicyclo(3.2.1)octane, i.e. reaction of cis-2,S-bis-(tosyloxymethyl)tetrahydrofuran with benzylamine to give 3-benzy1-8-oxa-3- azabicyclo(3.2.1 )octane which can -.then be debencis-2,5-Bis-(tosyloxymethyl)tetrahydrofuran, represented by formula (II), (500 grams, 1.135 moles) and 250 grams liquid ammonia in 2 liters of absolute ethanol were heated at C. for 1.52 hours at 600-650 psig. The reaction mixture was cooled and treated with a methanolic sodium hydroxide solution (65 grams NaOH in 300 ml of methanol). The salt was filtered off and washed with ether. The filtrate and ethereal washings were combined and the solvents were stripped at atmospheric pressure. The product 8-oxa-3- azabicyclo(3.2.1)octane, represented by formula (III), was-distilled at 177.5C.

EXAMPLE 3 8-Oxa-3-Azabicyclo(3.2.l )Octane Hydrochloride (1V) As soon as the product represented by formula (111) was distilled, it was dissolved in diethyl ether and HCl gas bubbled through slowly. The product 8-oxa-3- azabicyclo(3.2.l)octane hydrochloride had a melting point of 202204C. and is very stable.

Analysis for C H NOCI. Calculated: C, 48.16%; H, 8.09%; N, 9.36%; Cl, 23.70%. Found: C, 47.95%; H, 8.06%; N, 9.45%; Cl, 23.50%.

EXAMPLE 4 8-Oxa-3-Azabicyclo(3.2.1)Octane Hydroacetate A mixture of 30 grams (0.015 mole) of N-benzyl-8-. oxa-3-azabicyclo(3.2. 1 )octane, 1.0 gram of 10% palladium on charcoal, and 225 ml of glacial acetic acid was shaken in a Parr low pressure hydrogenator at 55C. and an initial hydrogen pressure of 80 psig. Within 30 minutes the hydrogen uptake was complete. The catalyst was removed by filtration and the solvent removed.

on a rotary evaporator. The residue was diluted with ethyl acetate and cooled. The product 8-oxa-3 azabicyclo( 3.2.1 )octane hydroacetate was collected by filtration, washed with ethyl acetate and dried over P to obtain a white solid, having a melting point of 132-133C.

All of the other compounds within the scope of the present invention, represented by formula (a) above, can be prepared in accordance with the principles and processes illustrated in the following Examples 5 to 56, with particular reference to types of reactions, types of reactants, ratios of reactants, reaction solvents, reaction times, temperatures, and other conditions cited. The compounds, represented by formula (a) above where R is an acyl or substituted acyl radical, are readily prepared by reacting azabicyclo(3.2.l)octane hydrochloride with an equal mole portion of an acyl chloride corresponding to the R substituent desired in a suitable solvent, such as an aqueous sodium hydroxide solution or benzene or other indicated solvents as illustrated in Examples 5 to 35. When substituent R of the compounds represented by formula (a) above is other than acyl, the subject compounds can be prepared by reacting the ditosylate compound represented by formula (11) with an excess of an amine corresponding to the R substituent desired in a suitable solvent, such as triethylene glycol dimethyl ether as illustrated in Examples 36 to 56.

EXAM PLE 5 3-Phenylacetyl-8-Oxa-3-Azabicyclo( 3.2.1 )Octane Phenylacetyl chloride (15.46 grams, 0.1 mole) (Aldrich Chemical Co., Inc., Milwaukee, Wis.) was slowly added to a mixture of 8-oxa-3-azabicyclo(3.2.1)octane hydrochloride (product of Example 3) (14.96 grams, 0. 1 mole) and sodium hydroxide (10 grams) in 300 ml water at 10C. After the addition of phenylacetyl chloride, the reaction mixture was stirred at room temperature for 2 hours. The crystalline solid (22.1 grams,- 95.6%) which separated was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30-60C.) and diethyl ether (v/v) to yield the product 3- phenylacetyl-8-oxa-3-azabicyclo)3.2.1)octane which had a melting point of 106l06.5C.

Analysis for C H NO Calculated: C, 72.70%; H, 7.41%; N, 6.06%. Found: C, 72.50%; H, 7.69%; N, 6.16%.

EXAMPLE 6 p-Chlorobenzoyl chloride (0.07 mole, 12.26 grams) (Aldrich Chemical Co., lnc., Milwaukee, Wis.) was slowly added to a mixture of 8-oxa-3- azabicyclo(3.2.1)octane hydrochloride (0.07 mole, 10.5 grams) and sodium hydroxide (7 grams) in 250 ml of water, at 10C. After the addition of p-chlorobenzoyl chloride, the reaction mixture was stirred at room temperature for 2 hours and then let stand at room temperature overnight. The product which separated as a solid (17.5 grams, yield) was filtered off, washed with water, and finally crystallized from a blend of about 30% petroleum ether (boiling point 30-60C.) and 70% diethyl ether (v/v). The product 3-(pchlorobenzoyl)-8-oxa-3-azabicyclo(3.2. 1 )octane had a melting point of 110-1 11C.

Analysis for C H O NCl. Calculated: C, 62.03%; H, 5.60%; N, 5.56%; C1, 14.08%. Found: C, 62.15%; H, 5.50%; N, 5.39%; Cl, 14.05%.

Using the procedure of Examples 5 and 6, 0.1 mole portions of 8-oxa-3-azabicyc1o(3.2.1 )octane hydrochloride [Compound (IV)] were reacted with 0.1 mole portions of other acyl chlorides listed. in Table 1 below in aqueous sodium hydroxide solution to produce the 3-acyl-8-oxa-3-azabicyclo(3.2.1 )octanes corresponding to the acyl radicals listed under the heading R in Table l.

TABLE I B-Acyl-B-Oxa-B-Azabicyclo(3.2.l)ctanes O N-R ANALYSIS Found Calculated C1 or C1 or crystallized Example Acyl chlorides R Y M.P. C. C 11 N S C H N S From 7 m-Chlorobenzoyl 0 81-82 61.94 5.43 5.36 14.20 62.03 5.60 5.56 14.08 30% Petroleum chloride* ether (boiling point 30-60C)- c 70% Diethyl ether (v/v) o 8 o-Chlorobenzoyl g 95-96 1.00 5.61 5.45 14.09 62.03 5.60 5.56 14.09 do chloride* 9 p-I'oluoyl chloride" CH I 79-00 72.55 7.21 6.01 72.69 7.41 6.05 do 10 rn-Chlorophenyl 1? 97-98 63.45 6.13 5.24 63.27 6.07 5.26 do acetyl chloride 32C 11 o-Chlorophenyl- 5? 123-125 63.45 6.13 5.18 63.27 6.07 5.26 6Q acetyl chloride 0 cc1 12 Cinnamoyl chloride* 9 103-104 73.93 6.05 5.70 74.04 7.04 5.75 do -cu=cuc-.

13 p-Tolylacetyl 9 124-125 73.70 7.07 5.70 73.44 7.00 5.70 do chloride cl-I 112C- 14 P- P 1 0 129-130 63.25 5.99 5.10 63.27 6.07 5.26 50% Ethanolacetyl chlonde c1 CH i J- 50% Diethyl ether (v/v) l5 y e y 4 R 133-140 73.52 7.73 5.63 73.44 7.80 5.70 Petroleum chlorlde CHzC- ether (boiling point 3060C)- ca; 700 Diethyl I 9 ether (v/v) 16 2-Quinoxal0Y1 I 137-139 66.72 5.64 15.28 66.89 5.61 15.59 50% Methylene chloride chloride-50% N Diethyl ether 0 (v/v) n I 17 9 112 1 chloride" c u c- 49-51 71.70 6.64 6.71 71.90 6.92 6.46 Methyl ether 18 m-Trlfluoromothil t 115-116 59. 21 4. 63 4 a5 55,94 4. 95 4, 9 Diethyl other bonzoyl chlor do" 3 9 vl chloride'" E l f? 78-80 59.32 5.02 6.32 14.50 59.17 5.07 6.27 14.36 Methyl who! hldrIch Chemical (20., Inc., Milwaukee, Wisconsin "Pierce chemical Co., Rockford, Illinois "0. T. Baker Chemical Co., Phillipsburg, New Jersey Producw oi Examplea 7 to 13 were -all crystallized from the combination of aolvents.

EXAMPLE 20 ether, the product 3-heptanoyl-8-oxa-3- azabicyclo(3.2.1)octane was obtained as a clear liquid. 3-Heptan9yl-8-0Xa-3-Azablcyclo(3-2-1109K109 Analysis for 0 11 010.. Calculated: c, 69.28%; H, l-leptanoyl chloride (14.86 grams, 0.1 mole) was N, 621% F0l1nd1C,69.33%; slowly added to a mixture of 8-oxa-3- 616%- azabicyclo(3.2.l )octane hydrochloride product of Ex- Using the Procedure of Example 20, mole P ample 3 (14.96 grams, 0.1 mole) and sodium hydroxide ti ns f 8-0 a-3-aZ y 0( c hy (10 grams) in 300 ml water, at 10C. After the addition ride [compound (IV)] were reacted with 0.1 mole porof heptanoyl chloride, the reaction mixture was stirred tions of other acyl chlorides listed in Table 11 below in for 2 hours and then left overnight at room temperaaqueous sodium hydroxide solution and extracting the ture. The product was extractedlrom the reaction mixreaction mixture with diethyl ether gave the 3-acyl-8- ture with diethyl ether and treated with DARCO G oxa-3-azabicyclo(3.2.l)octanes corresponding to the (activated carbon). After the removal of the diethyl acyl radicals listed under the heading R in Table 11.

T A B L E I I 3-Acyl-8-0xu-3-ltzabioyclo (3 2 1)Octanom h/N-R A n x 1. v 0 I 5 oun 41 cu m u Yield cryucullimd Example Acyl Chloridu R 14.? C. E5 ll 51 E ll 11 0 From 21 Hydrocinnamoyl Clear 73.39 7.61 5.70 73.44 7.00 5.70 90.5 (2) chloride" -C5H CH CH C- viacoui liquid 22 o-Ioluoyl chloride" I 3; Color- 72.48 7.58 5.92 72.69 7.41 6.05 93.0

' less H viscous 3 liquid less viscous 23 m-Toluoyl chloiride'" 93 Color- 72.09 7.46 6.05 72.69 7.41 5.93 97.0

' H3 liquid TABLE ll-Continued 3-Acyl-B-Oxa-3-Azabicyclo(3.2.l)0ctanea /N-R A N A L Y S I 5 Found Calculated Yield crystallized Example Acyl chlorides R M.P. "C. C H N C H N S From 24 Hexahydrobenzoyl ii 72-74 69.88 9.38 6.22 69.92 9.48 6.27 42.0 30! Petroleum chloride)" ether (boiling point: 30-60%?)- 70! Diethyl Q2 ether (v/v) 25 m-Methoxybenzoyl 54.5-55.5 67.81 7.16 5.58 67.99 6.93 5.06 87.0 do

chloride 26 Stearoyl chloride C H 8 51-53 75.80 11.81 3.59 75.93 11.95 3.69 80.0 do

27 Propionyl chloride" COlOr- 63.75 9.12 0.22 63.88 8.93 8.27 50.0 do

C 11 C lens liquid (on Itaudinq the product crystallized to loft: white cyrstals.

Purified by column chromatography (alumna/diethyl ether).

/P C-Cl I HCl O NH HC1+ L N (VIII) Nicotinoyl chloride hydrochloride (17.8] grams, 0.1

mole) was slowly added to a mixture of 8-oxa-3- azabicyclo(3.2.l octane hydrochloride-( 15 grams, 0.1 mole) and sodium hydroxide (15 grams) in 300 ml of water, at 10C. After the addition of nicotinoyl chloride hydrochloride, the reaction mixture was stirred for 2 hours and then left overnight at room temperature. The product was extracted from the reaction mixture with diethyl ether and the extract treated with DARCO G60 (activated carbon). After the removal of ether, the product was obtained as a clear liquid (10 grams, 46%

. yield) which crystallized. The product 3-nicotinoyl-8- oxa-3-azabicyclo(3.2.1)octane was recrystallized from a blend of about 30% petroleum ether (boiling point 3060C.) and 70% diethyl ether (v/v) to white crystals having a melting point of 48-49.5C.

50 Analysis for C H N O Calculated: C, 66.03%; H,

6.46%; N, 12.84%. Found: C, 66.05%, H, 6.44%; N, 12.66%.

EXAMPLE 29 3-(Acetylsalicyloyl )-8-Oxa-3- Azabicyclo(3.2 .1)Octane Eastman Kodak (30., Rochester, N.Y. "Aldrich Chemical (10., Inc., Milwaukee, Wisconsin "'K s K Laboratories, Inc., Plainview, N.Y.

o-Acetoxybenzoyl chloride (0.1 mole, 1985 grams) was slowly added to a mixture of 8-oxa-3- azabicyclo(3.2.l)octane (0.1 mole, 11.13 grams) and triethylamine (0.1 mole) in ml of benzene at 20C. The reaction mixture was stirred 2.5 hours at 25C. The salt was filtered off and washed with benzene. After re moval of benzene, the product was obtained as a viscous liquid which was purified by column chromatography (alumina). Impurities were eluted with ether and the product with methanol to yield the product represented by formula (1X).

Analysis for C H NO Calculated: C, 65.44%; H, 6.23%; N, 5.09%. Found: C, 65.55%; H, 6.05%; N, 5.05%.

EXAMPLE 30 3-(o-Carboxybenzoyl)-8-Oxa-3- Azabicyclo(3.2.1 )Octane O NH I, '"9 aL l l 3 O N C HQOC EXAMPLE 3 3-( 1-Adamantanecarbonyl)-8-Oxa-3- Azabicyclo(3.2.1)ctane C-Cl l-Adamantanecarbonyl chloride (19.87 grams, 0.1 mole, pulverized) (Aldrich Chemical Co., Inc., Milwaukee, Wis.) was added to a mixture of 8-oxa-3- azabicyc1o(3.2.1 )octane hydrochloride 14.96 grams, 0.1 mole) and sodium hydroxide. grams) in 300 ml water. The reaction mixture was heated at 30C. for 3 hours and then left overnight at room temperature. The product (22 grams) was filtered off, washed with water, and finally recrystallized from a blend of about 30% petroleum ether (boiling point 30-60C.) and 70% diethyl ether (v/v). The product had a melting point of 134136C.

Analysis for C H NO Calculated: C, 74.14%; H, 9.15%; N, 5.08%. Found: C, 74.10%; H, 9.21%; N, 5.06%.

EXAMPLE 32 3-( Phenylglyoxylyl )-8-Oxa-3- Azabicyclo(3.2.1)0ctane (III) 9 O 1 II EXAMPLE 33 3-(o-Hydroxybenzoyl)-8-Oxa-3- Azabicyclo(3.2.l )Octane Salicylyl chloride (24 grams, 0.15 mole) was slowly added to a solution of 17.0 grams (0.15 mole) of the compound represented by formula (111) in 25 ml of benzene at 10C. The reaction mixture was stirred for 1 hour and then left overnight at room temperature. The HCl salt of the compound represented by formula (III) illustrated by formula (IV) was filtered and the benzene solution was concentrated to dryness. The product represented by formula (X111) (6.0 grams) crystallized on standing and was recrystallized for ethanol-diethyl ether (1:1 The product had a melting point of 155157C.

Analysis for C H, O N,. Calculated: C, 66.93%; H, 6.48%; N, 6.00%. Found: C, 67.25%; H, 6.49%; N, 6.07%.

EXAMPLE 34 3-Benzenesulfonyl-8-Oxa-3-Azabicyclo(3.2.1 )Octane a thermometer and was connected to a condenser set for downward distillation.

1n the flask was placed 25 grams (0.152 mole) of methyl benzoyl formate and 25 ml xylene and the mixture was heated at 130C. Then, the reactant repredenser terminating in a still head. The still head carried 6 l3enzenesulfonyl chloride 17.7 grams, 0.1 mole) dissolved in 15 ml of pyridine was slowly added to a solution of the compound represented by formula (111) in 15 ml of pyridine at 5C. The reaction'mixture was stirred for 2.5 hours at 5C. and. then poured over an ice-water mixture which effected a precipitate. The crude product was filtered off and washed with water many times to remove excess pyridine and pyridine hydrochloride. The product 3-benzenesulfonyl-8-oxa-3- azabicyclo(3.2.l)octane recrystallized from ethanol had a melting point of 166-'168C.

Analysis for CQH N OS. Calculated: C. 56.89%; H, 5.97%; N, 5.53%; S, 12.71%. Found: C, 56.83%; H, 5.82%; N, 5.52%; S, 12.83%.

EXAMPLE 35 3-(N-Phenylcarbamoyl)-8-Oxa-3- Azabicyclo( 3.2.1 )Octane Phenyl isocyanate (1 1.9 grams, 0.1 mole) dissolved in 25 ml of benzene was slowly added to a solution of the compound represented by formula (III) (11.3 grams, 0.1 mole) in 25 ml of benzene at C. The reaction mixture was stirred for 2 hours at l4l6C. and then left overnight at room temperature. The product, white crystals, was filtered off, washed with benzene, and recrystallized from ethanol. The product 3-(N- phenylcarbamoyl)-8-oxa-3-azabicyclo(3.2.1 )octane had a melting point of 184-l86C.

Analysis for C H N O Calculated: C, 67.22%; H, 6.94%; N, 12.16%. Found: C, 67.45%; H, 7.01%; N,

bis(tosyloxymethyl)tetrahydrofuran (0.4 mole, 176 grams), and 700 ml of absolute ethanol were charged into a one gallon autoclave andheated at 150C. for 2 hours and 200 psig pressure. The reaction mixture was cooled and treated with a methanolic sodium hydroxide solution (0.8 mole, 32 grams/300 ml). The resulting 'tosylate salt was filtered and the excess allylamine and ethanol were stripped from the filtrate at atmospheric pressure. 3-Allyl-8-oxa-3-azabicyclo(3.2.1)octane dis-.

tilled as a colorless liquid (terminal pot temperature l25C./O.5 mm Hg). The product was dissolved in ether and anhydrous HCI bubbled in the solution. 3-

Allyl-8-oxa-3-azabicyclo(3.2.l )octane hydrochloride,"

16 represented by formula (XVll). which precipitated as white crystals, was filtered and washed with ether. The product had a melting point of 169-171C.

Analysis for C H NOCI. Calculated: C, 56.98%; H. 8.50%; N, 7.40%; Cl. 18.69%. Found: C. 57.21%; H. 8.50%; N, 7.32%; Cl, 18.90%.

EXAMPLE37 3-Cyclohexyl-8-Oxa-3-Azabicyclo(3.2.1)Octane Hydrochloride Cyclohexylamine (0.6 mole, 59.6 grams) was reacted with the ditosylate represented by formula (11) (0.2 mole, 88.1 grams) in ml of Ansul 161 (triethylene glycol dimethyl ether) at C. for 2 hours. The reaction mixture was cooled to room temperature and neutralized with a methanolic sodium hydroxide solution (16 grams NaOH in 200 ml CH OH). Sodium tosylate was filtered off and the excess cyclohexylamine and Ansul 161 were stripped from the filtrate under aspirator pressure. 3-Cyclohexyl-8-oxa-3- azabicyclo(3.2.1)octane, identified herein as product (XVlll), was distilled under vacuum (terminal pot temperature 280C./0.1 mm Hg).

Product (XVIll) (11.12 grams) was dissolved in 200 ml of ether and anhydrous hydrogen chloride was bubbled through the solution. The 3-cyclohexy1-8-oxa-3- azabicyclo(3.2.1)octane hydrochloride, represented by the formula (XIX), was filtered, washed with ether, and dried.

Analysis for C H NOCI. Calculated: C, 62.18%; H, 9.57%; N, 6.04%; Cl, 15.30%. Found: C, 61.74%; H,

9.54%; N, 6.09%; CI, 15.47%.

EXAMPLE 38 3-Phenyl-8-Oxa-3-Azabicyclo(3.2.1)Octane Aniline (1.2 mole, 111.8 grams) was added to a mixture of 2,5-bis(tosyloxymethyl)tetrahydrofuran, represented by formula (11), (0.4 mole, 176.2 grams) and 300 ml ofAnsul 161 (triethylene glycol dimethyl ether) 3,856,783 l7 18 and the reaction mixture heated for 4 hours at 185C. neutralized with a methanolic sodium hydroxide solu- The reaction mixture was cooled to room temperature tion (0.429 mole. 17.14 grams NaOH in 200 ml and neutralized with a methanolic sodium hydroxide CH OH)while stirring for 15 minutes.The solvents and solution (32 grams NaOH in 300 ml CH OH). Sodium excess starting amine were distilled from the reaction tosylate was filtered and Ansul 161 and excess aniline 5 mixture under aspirator pressure. The residue was filstripped from the filtrate under aspirator pressure. 3- tered collecting the sodium p-toluenesulfonate. The fil- Pheny1-8-oxa-3-azabicyclo(3;2.l)octane, repre nted trate was distilled collecting one fraction (terminal pot by formula (XX), was distilled at 1 13C./0.15 mm Hg. temperature 280C./0.1 mm Hg). The distillate which The product solidified on standing and after recrystallisolidified was recrystallized from methanol obtaining zation from methanol had a melting point of 84-85C. 1O 3-(p-chlorophenethyl)-8-oxa-3- Analysis for C H NO. Calculated; C, 76.15%; H, azabicycl0(3,2.1)0ctane 7.99%; N, 7.40%. Found: C, 76.26%; H, 8.14%; N, 3-(p Chlorophenethyl)-8-oxa-3- 7.31% azabicyclo(3.2.1)octane (0.133 mole, 32.6 grams) was dissolved in 2 liters-of anhydrous diethyl ether and an- EXAMPLE 39 15 hydrous hydrogen chloride was bubbled through solu- I 3.21 O t tion to obtain a fine white precipitate. The precipitate 3 eny l -lydrtf hl iifig c we was collected by filtration, washed with diethyl ether,

and dried. The product obtained, 3-(pchlorophenethyl)-8-oxa-3-azabicyclo(3.2.1 )octane hysffnted by m lxx) (0122 grams) was drochloride, represented by formula (XXIII), had a dissolved in diethyl ether and anhydrous hydrogen melting pOimof]94 5 195 50C chloride was bubbled through the solution. The prod- Ana|ysis f NOG Calculated: C, 58.34%; H,

uct 3-phenyl-8-oxa-3-azabicyclo(3.2.1)octane hydro- 664%; N, 4.86%; CI 24.61% FoundI C, 584476; H chloride was filtered off, washed with diethyl ether, and 708%; N 470%; CL 24-40% dried. The product had a melting point of l68-170C. 25

Analysis for C H NOCl. Calculated: C, 63.85%; H,

7.15%; N, 6.21%; CI, 15.71%. Found: C, 63.61%; H,

7.44%; N, 6.04%; CI, 15.67%.

3-Phenyl-8-oxa-3-azabicyclo(3.2.1)octane, repre- Using the procedure in the first paragraph of Example 40, 0.05 molev portions of 2,5-bis(tosyloxymethyl)- tetrahydrofuran, represented by formula (II), is reacted with 0.15 mole portions of amines listed in Table III for 2 hours in trieth lene 1 col dimeth lether to roduce EXAMPLE 4O various compou nds o fthe preseni inventiori corre- 3-(p-Chlorophenethyl)-8-Oxa-3- sponding to the aralkyl radicals listed under the head- Azabicycl0(3.2. 1 )Octane Hydrochloride ing R in Table III. In Examples 42 and 44 to 51, the 3- cH 0so c H cH 2) Hcl t NCH CH QCl 'YHCl (XXIII) pChlorophenethylamine (0.643 mole, grams) aralkyl-8-oxa-azabicyclo(3.2.1)octane compounds obwas added to a mixture of 2,5-bis(tosyloxymethyl)tettained by the above process were converted to their hyrahydrofuran (0.214 mole, 99.6 grams) and 200 ml of drochloride salts by bubbling anhydrous hydrogen Ansul 161' (triethylene; glycol dimethyl ether) and 55 chloride through an'ethei'eal solution of said 3-aralky1- stirred the reaction mixture for 3 hours at C. The 8-oxa-azabicyclo(3.2.1)octane compounds by the proreaction mixture was cooled to room temperature and cess set forth in the second paragraph of Example 40.

TABLE III 3-Aral1tyl-8-Oxa-3-Azabicyc1o (3. 2 1) Octane O N-R ANALYSIS Pound Calculated Example Amine Reactant R 5.2. or M.P.' C H N CY C H N C1 41 -Meizhylphenethyl r CH 120.5-120.8C/ 77.73 9.38 5.72 77.89 9.15 6.06

amine 3 0.44-0.46 mm Hg 42 Met:l'iy.Iphenetzhy1 I "1 201.5-202C 67.39 8.46 5.40 13.43 67.27 8.28 5.23 13.24

I amine HCI' H H- 43 3.4-Dimothoxy- (1 68.5-69C 69.24 8.44 5.05 69.28 8.36 5.05

PhenethYl atune 3% Z T TABLE III-Continued A u A r. x s 1 s Found Calculated Example Amine Reactant: R 5.1. or M.P. C H Cl C bl N C1 44 3,4-Dimethoxy- 14:5 225-226C phenethyl amine HCl 4 ca o -crr ca Benzyl amine 1a5-1e5.5 65.08 7.30 5.78 14.57 65.13 7.57 5.94 14.79

HCl- CH 46 Phenethyl amine 217.5-2l9c 14.04 13.97

47 -Chloro heneth 1 194.5-195.sc 58.44 7.08 4.70 24.40 58.34 6.64 4.86 24.61

p P y act-c1 "'-\-CH ca am1ne 2 2 48 p-Methoxyphenethyl zoo-201w 63.25 7.79 4.76 12.59 63.48 7.02 4.94 12.94

amine HCl-CH 0' a cu 49 am-Dimethylphenethyl 1' E 244.5-245c 68.40 8.88 4.08 12.60 68.19 0.59 4.97 12.58

amine HCl- CHZ-C- v 50 B-Methylphenethyl 166-167C 67.43 9.37 5.12 13.09 67.27 0.29 5.23 13.24

amine HCl' QHCHT s1 -ueth l- -chlom- 205-2o7c 60.08 6.82 4.51 23.42 59.75 6.69 4.64 23.56

phene thyl amine If desired, 3-benzyl-8-oxa-3-azabicyclo( 3.2.1 )octane. can be debenzylated to form 8-oxa 3- azabicyclo(3.2.1)octane by dissolving the said benzyl derivative in absolute alcohol and then reacting same with hydrogen in the presence of a suitable amount of palladium on carbon (normally about 2% of 10% palladium or carbon'based on the total weight of the reaction mixture is sufficient under pressure of about psig and at about 70-75C.

grams NaOH in ml CH OH) was added to the reacperature 290C., vapor temperature C./0.2 mm

Hg). The distillate was placed on silica gel and eluted first with methylene chloride (impurity removed) and finally with diethyl ether to obtain the pure 3-[1-(2- 35 thienyl)isopropyl]-8-oxa-3-azabicyclo(3.2.1)octane. 3-[1-(2-Thienyl)isopropyl]-8-oxa-3- EXAMPLE azabicyclo(3.2.l )octane (4.77 grams) was dissolved in 3-[1-(2-Thienyl)lsopropyll-8-Oxa-3- anhydrous diethyl ether and anhydrous hydrogen chlo- Azabicyclo(3.2.l )Octane Hydrochloride ride was bubbled through the solution effecting a white 1) 7 1H CHCH CH2OSO2C6H4CH3-E i 2 3 o l L cH os 0 c a cH 2) Hcl 1 Y" l l o NCHCH 'HCl CH (XXV) 3 B-(2-Thi |)i 1 mi (0963' mole, 3 9 crystalline precipitate. The precipitate was collected by grams) was added to a mixture of 2,5- filtration, washed with diethyl ether, and dried. The bis(tosyloxymethyl)tetrahydrofuran (0.063 mole, 27.7 P y P PYU- grams) and tributylamine (0.126 mole, 23,3 g i azabicyclo(3.2.1)octane hydrochloride represented by ml of Ansul 161 (triethylene glycol dimethyl 5 formula(XXV)hadamelting point of 232.5-233.5C.

ether). The reaction mixture was stirred for 3 hours at C. and cooled to room temperature. Then a methanolic sodium hydroxide solution (0.126 mole, 5.03

Analysis for C H NOCIS. Calculated: C, 57.02%;

H, 7.36%; N, 5.12%; S, 1 1.71%; C1, 12.95%. Found: C. 57.13%; H, 7.40%; N, 5.04%; S, 11.61%; Cl, 12.96%.

e -21 EXAMPLE 53 3-Dimethylaminopropyl-8-Oxa-3- Azabicyclo(3.2.l )Octane Dihydrochloride -CH c H cu T 2 2 6 4 3 1 1) (CH3) and the combined extracts stripped of diethyl ether.

The residue was distilled and 3-dimethylaminopropyl- 8-oxa-3-azabicyclo(3.2.l )octane was obtained.

3-Dimethylaminopropyl-8-oxa-3- (XXVI) Dimethylaminopropylamine l .2 mole, 122.8 grams) was slowly added over minutes to a mixture of 2,5-

bis-(tosyloxymethyl)tetrahydrofuran and 300 ml of Ansul l6l (triethylene glycol dimethyl ether) while maintaining the reaction temperature between l-l C. Continued heating for 2.5 hours after addition. Stripped solvent and excess dimethylaminopropylamine from reaction mixture under aspirator pressure (terminal pot temperature C). A metha-' nolic sodium hydroxide solution (0.8 mole, 32 grams NaOH in 300 mlCH OH) was added to the pot residue which produced a-precipitate. Filtered the tosylate salt and distilled the filtrate rapidly (terminal pot temperature 225C.) collectingone fraction.

The distillate was dissolved in 2 liters of anhydrous diethyl ether and anhydrous hydrogen chloride was bubbled throughthe solution producing a precipitate. The precipitate was collected byzfiltration, washed with ether and neutralized with aqueous sodium hydroxide. The aqueous mixture was extracted with diethyl ether 2 HCl EXAMPLE 54 3-(2-Aminoethyl)-8-Oxa-3-Azabicyclo( 3.2. l )Octane Dihydrochloride (XXXII) and 3,3-Ethylene-bis[8-Oxa-3-Azabicyclo(3.2.1)Octane] Dihydrochloride (XXXI) 0 NCH CH NHZ (XXVII) HCl (XXXII) O NCH CH N O (XXX) HCl NCHZCH NH '2 HCl (XXXI) '2 HCl Ethylenediamine (3.0 moles, 180.3 grams) was reacted with the compound represented by formula (11) (1.0 mole, 440.5 grams) in 550 ml Ansul 141 (diethylene glycol dimethyl ether) at 152C. for 2 hours. The Ansul 141 was stripped from the reaction mixture and a methanolic sodium hydroxide solution (2.0 moles, 80 grams NaOH in 500 ml CH OH) was added. The resulting mixture was stirred for 15 minutes at room temperature and the resulting tosylate salt was filtered off. Then the solvents were stripped and the residue was distilled very rapidly and one fraction was collected (terminal pot temperature 250C, vapor temperature 210C./0.1 mm Hg).

Solids crystallized from the distillate on standing were collected by filtration and recrystallized from diethyl ether, and then methanol. Upon drying, a white crystalline material having a melting point of l00.5llC. was identified as 3,3-ethylene-bis[8- oxa-3-azabicyclo(3.2.1 )octane], represented by formula (XXX). 1

Analysis for C H N O Calculated: C, 66.63%; H, 9.59%; N, 11.10%. Found: C, 66.70%; H, 10.04%; N, 11.10%.

The compound 3,3-ethylene-bis[8-oxa-3- azabicyclo(3.2.1 )octane] dihydrochloride, represented by formula (XXXl), was prepared by dissolving the compound represented by formula (XXX) (0.7 grams, 0.0384 mole) in diethyl ether and bubbling in anhydrous hydrogen chloride. The product represented by formula (XXXl) had a melting point of 313C.

Analysis for C H N O Cl Calculated: C, 51.69%; H, 8.06%; N, 8.61%; C1, 21.80%. Found: C, 51.58%; H, 8.00%; N, 8.43%; Cl, 21.77%.

The filtrate, from which the compound represented by formula (XXX) was isolated, was stripped of solvents and distilled collecting 81.7 grams of 3-(2- aminoethyl)-8-oxa-3-azabicyclo(3.2.1 )octane (b.p. 68.5C./0.07 mm Hg). 27 Grams of 3-(2-aminoethyl)- 8-oxa-3-azabicyclo(3.2.1)octane were dissolved in 500 ml of anhydrous diethyl ether. Anhydrous hydrogen chloride was passed through the resulting ethereal solution to obtain a fine crystalline precipitate. The precipitate was filtered off, washed with anhydrous diethyl ether, and dried yielding 33.9 grams of 3-(2- aminoethyl)-8-oxa-3-azabicyclo( 3.2.1 )octane dihydrochloride, represented by formula (XXXll), having a melting pont of point 26l.5-262.SC.

Analysis for C H N OCl Calculated: C, 41 93%; H,

7.92%; N, 12.23%; Cl, 30.94%. Found: C, 42.05%; H, 8.21%; N, 12.23%; Cl, 30.91%.

EXAMPLE 55 3-(6-Aminohexamethylene )-8-Oxa-3- Azabicyclo(3.2.l )Octane (XXVlll) and 3 ,3 -Hexamethylene-Bis[8-O xa 3- Azabicyclo(3.2.l )Octane] (XXlX) Hexamethylenediamine (0.4 mole, 46.5 grams) was reacted with the compound represented by formula (11) (0.4 mole, 176.2 grams) in 400 ml ofAnsul 161 (triethylene glycol dimethyl ether) at C. for 2 hours. The reaction mixture was cooled and treated with a methanolic sodium hydroxide solution (32 grams NaOH in 400 ml CH OH). The tosylate salt was filtered and after stripping the Ansul 161, the residue was distilled (terminal pot temperature 280C, vapor temperature 230C./0.1 mm Hg). Solids which formed in the distillate were collected by filtration and recrystallized from methanol/water. These solids were characterized as 3,- 3-hexamethylene-bis[8-oxa-3- azabicyclo(3.2.l )octane], represented by formula (XXlX).

The compound represented by formula (XXlX) (0.015 mole, 4.76 grams) was dissolved in 250 ml anhydrous diethyl ether and anhydrous hydrogen chloride was bubbled through the solution producing a precipitate. The precipitate started to coagulate, the diethyl ether was decanted and fresh anhydrous diethyl ether was added. The mixture triturated and the precipitate collected by filtration obtaining 3,3'-hexamethylenebis[8-oxa-3-azabicyclo(3.2. 1 )octane] dihydrochloride having a melting point of 282 283C.

Analysis for C H N H, 2Cl Calculated: C, 56.68%;H, 8.99%; N, 7.35%; Cl, 18.59%. Found: C, 56.16%; H, 9.19%; N, 6.92%; C1, 18.67%.

The filtrate, from which the compound represented by formula (XXIX) was isolated, was redistilled under reduced pressure collecting the 3-(6- aminohexamethylene-8 oxa-3- azabicyclo(3.2.1)octane, represented by formula (XXVlll) having a boiling point of 92.2C./0.04 mm Hg. The dihydrochloride salt of(XXVlll) was prepared and had a melting point of 244-245C.

Analysis for C H NOC1 Calculated: C, 50.52%; H, 9.19%; N, 9.82%; Cl, 24.86%. Found: C, 50.42%; H, 9.27%; N, 9.90%; Cl, 24.61%.

EXAMPLE 56 3-(Z-Guanadinoethyl)-8-Oxa-3- Azabicyclo(3.2.1)0ctane Hydrosulfate Monohydrate (XXVII) T 181541250 NCH CH NHCNH H O tion of methyl mercaptan. The reaction mixture was stirred for 2.75 hours at 85C., and after cooling at room temperature concentrated hydrochloric acid EXAMPLE A Salicylyl Chloride A mixture of 10 grams of salicylic acid, 7 ml of thio- (0077 mole 7.62 grams) was added and let Stand for nyl chloride and 0.02 grams of aluminum chloride were 17 hours.

2.0 grams of yellowish solid was collected by filtration and the water was removed from the filtrate using a rotatory evaporator under aspirator pressure. 200 ml of methanol was added to the viscous residue which effected a white granular precipitate. Addition of more methanol effected another crop of the desired crystals of 3-(Z-guanadinoethyl)-8-oxa-3- azabicyclo(3.2.l )octane hydrosulfate monohydrate.

Analysis for C H N O S. Calculated: C, 34.38%; H, 7.06%; N, 17.82%; S, 10.20%. Found: C, 34.22%; H 6.88%; N, 17.62%; S, 10.52%.

The condensation-type products of the present invention, such as when R in formula (a) above is arylene dicarbonyl-8-oxa-3-azabicyclo(3.2.1)octane or alkylene dicarbonyl-8-oxa-3-azabicyclo(3.2.1)octane, can

be prepared by reacting at 10 to C. two moles of 8- oxa-3-azabicyclo(3. 2.l )octane with one mole of the desired arylene or alkylene diacid chloride, such as terephtholoyl chloride or adipyl chloride in a solvent, such as benzene in the presence of a stoichiometric quantity of a tertiary amine, such as triethylamine to react with the hydrogen chloride which is generated by the reaction. The resulting triethylamine hydrochloride can be filtered off. The filtrate containing the desired product is then vacuum-stripped to remove the benzene and the residue obtained is crystallized from benzene-diethyl ether (1:1 v/v) to yield the desired product.

The physiologically or pharmacologically acceptable acid addition salts of the compounds of the present invention are included within this invention. These acid addition salts are prepared by known processes, such as illustrated in several of the preceding examples, which involve reacting a free base compound of the present invention with an appropriate acid in a suitable solvent, for example, diethyl ether or ethyl alcohol. For example, among the mineral acids that can be used to prepare the subject acid addition salts are hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid. Suitable organic acids that can be used to prepare the subject acid addition salts are, for example, acetic acid, methanesulfonic acid, propionic acid, maleic acid, fumaric acid, tartaric acid, citric acid, and benzoic acid.

As shown in the above examples, the compounds of the present invention can be suitably purified by conventional methods, for example, by distillation, crystallization, or chromatography as indicated.

The acyl chloride reactants used to prepare the products of the present invention represented by formula (a) herein above where R is an acyl radical or substi tuted acyl radical can readily be prepared from their corresponding acid compound by reaction with an excess of a suitable agent, such as thionyl chloride or phosphorus halides, such as PO, and, PCl All .of the acyl chloride reactants required for the preparation of the subject substituted compounds can be prepared by suitably using one of the well-known methods illustrated in Examples A to J. However, most of the acyl chlorides needed to prepare the subject compounds are commercially available.

heated at 4045C. for 1.5 hours. The excess thionyl chloride was removed in vacuum and salicylyl chloride was obtained.

EXAMPLE B Nicotinoyl Chloride-Hydrochloride A mixture of grams of nicotinic acid and 180 ml of thionyl chloride were heated at 5565C. for 3.5 hours. The excess thionyl chloride was removed in vacuum and nicotinoyl chloride-hydrochloride was obtained.

EXAMPLE C m-Methoxybenzoyl Chloride A mixture of 50 grams of m-methoxybenzoic acid and ml of thionyl chloride were heated for 3 hours at 70C. The excess thionyl chloride was stripped under vacuum to yield the desired acyl chloride product. The product m-methoxybenzoyl chloride distilled at 7778C./12 mm Hg.

The procedure used to prepare m-methoxybenzoyl chloride (Example C) was employed to synthesize the acyl chlorides listed in Table IV. The molar ratio of thionyl chloride to acid reactant used, for example, can be within the range of 2:1 to 4:1. The exact amount of thionyl chloride used is not critical so long as it is in substantial molar excess in relation to the acid reactant. After the desired reaction is complete, the excess thionyl chloride is easily removed by stripping under vac- (1) The o-chloruphenyl acetic acid and thionyl chloride were heated at l l(lC. for 3 hours and the product used without further purification.

('2) The excess thionyl chloride was removed under vacuum and the product was used without any further purification.

Evaluation in laboratory animals indicates that the present compounds possess analgesic and/or antiinflammatory activity when administered in a therapeutically effective amount. The effectiveness and dosage required vary, as is customary in this art, with the species being treated, particular disorder being treated, weight of the animal, and the route of administration. In accordance with the present invention, the subject compounds are administered at doses from about 1.0 milligram to 600 milligrams per kilogram body weight 1 to 4 times a day. A more preferred dose is from about Rat lnflamed Paw Pressure Test (Analgesic Test) Non-fasted albino rats in the weight range of 160 to l 80 grams are used. The experimental drugs are administered orally 10 ml/kg volume). Immediately after the administration, 0.1 ml of a 1% sodium carrageenan (Marine Colloids, lnc., Springfield, NJ.) in a sterile 0.9% aqueous solution of sodium chloride is injected into the subplantar region of the right hind paw. At a specific time post drug administration, the animals right hind paw is placed between two plastic-grooved discs which are compressed by air pressure, and the amount of pressure required to induce vocalization and/or bitting of the apparatus is recorded. The average pressure requirements for a drug-treated group of 6 animals is compared to that of a control group which received 0.9% saline in place of the drug. The percent change of the test group from the control group is calculated. 3-Benz0yl-8-oxa-3-azabicyclo(3.2. l )octane when evaluated in this test had an ED, of 315 mg/kg body weight Acetylsalicyclic acid in the same test had an ED of 1,500 mg/kg body weight, and codeine sulfate had an ED of l67 mg/kg body weight. 3- Phenylacetyl-8-oxa-3-azabicyclo(3.2. l )octane when evaluated in this test had an ED; of 220 mg/kg body weight.

Mouse Acetylcholine Writhing Test (Analgesic Test) Female albino mice weighing l8 to 25 grams are administered the test drugs orally (10 ml/kg volume). One-half hour after administration of the test drug, acetylcholine bromide (l 1.0 ml/kg) is administered intraperitoneally (10 ml/kg) and the time to writhing recorded. The observation period extended for 10 minutes. Control animals dosed with 0.9% saline (10 mg/kg) are tested simultaneously. The percent inhibition of writhing is calculated from the number that did not writhe in 5 minutes post injection of the acetylcholine bromide.

3-Benzoyl-8-oxa-3-azabicyclo(3.2. l )octane when evaluated in this test had an ED of 500 mg/kg body weight. Acetylsalicylic acid in the same test had an ED of 150 mg/kg body weight and codeine sulfate had an ED of 46 mg/kg body weight. 3-Phenylacetyl-8- oxa-3-azabicyclo(3.2.l )octane when evaluated in this test had an ED of 195 mg/kg body weight. 3-(m- Chlorobenzoyl )-8-oxa-3-azabicyclo( 3.2.1 )octane when evaluated in this test had an ED of 460 mg/kg body weight.

Rat Carrageenan Edema Test (Anti-inflammatory Test) Colloids. lnc., Springfield, NJ.) in a sterile 0.9% aque-' ous solution of sodium chloride is injected into the subplantar area of the right hind paw and the foot volume measured by volume displacement. The foot volume is measured again at 4 hours post injection of the drug and the percent change in volume when compared to a control group receiving 0.9% saline instead of the drug is calculated.

3-Phenylacetyl-8-oxa-3-azabicyclo( 3.2. l )octane when evaluated in this test had an ED of 550 mg/kg body weight. Acetylsalicylic acid in this test had an ED of l 10 mg/kg body weight. Codeine sulfate exhibited no activity in this test. 3-Benzoyl-8-oxa-3- azabicyclo(3.2.l)octane when evaluated in this test 7 had an ED, of 600 mg/kg body weight.

' The designation ED is used hereinabove to designate a dose level which showed significant activity in 50% of the animals tested.

As the compounds within the scope ofthis invention are effective upon oral administration, they can be compounded into any suitable oral dosage form, such as in tablet, capsule, syrup, elixir, suspension or other solid or liquid forms that can be prepared by procedures well known in the art. Thus, the subject novel compounds can be mixed with a suitable diluent, such as lactose or kaolin, and encapsulated; or they can be combined with suitable binding agents and expanding agents and compressed into tablets. In addition, a liquid pharmaceutical may be obtained by dissolving, dispersing, or suspending novel compounds of this invention with a suitable flavored liquid. The present compounds are also considered active upon parenteral and rectal administration.

Examples of formulations for preparing tablets. capsules, liquids, parenterals, and suppositories containing the compounds of the present invention are described below. Obviously, it will be recognized by one skilled in the present art that the following formulations represent only one method of preparing such pharmaceutical compositions and obviously the size of the tablet or capsule or the strength of the dosage form may be suitably varied in order to satisfy the particular requirements, such as dosage level indicated. For example, each dosage unit may conveniently contain from about 15 milligrams to 5,000 milligrams of the active ingredient admixed with a diluent amount of a pharmaceutically acceptable carrier. Any of the well-known suitable pharmaceutical carriers can be used to prepare acceptable dosage forms so as to provide an effective amount or therapeutically effective amount of the compound to be administered.

Suppository Containing 250 mg of 8-Oxa-3-Azabicyclo(3.2.l )Octane 8-Oxa-3-Azabicyclo(3.2.l )Octane Cocoa Butter Make of Such No. I00

0.250 gram l.750 grams Suspension Containing mg per 5 cc of 3-Benzoyl-8-Oxa-3-Azabicyclo( 3.2.1 )Octane 3-Benzoyl-8-0xa-3-Azabicyclo(3.2.1)Octane 20 grams Tragacanth 50 grams Amaranth l0 grams Syrup Wild Cherry 60 ml Distilled Water. q.s. I000 ml Capsule Containing 250 mg of 3,3- llcxnmclhylene-llisltl-Oxn-B-Aznbicyelol3.2.l )Ocnmel 3.3'-Hcxamethylenc-BislX-Oxa-J-Azabicyclo (3.2.l )Octane] Powdered Lactose D.T.Dt Capsules No. 1000 250 mg l mg Mix the ingredients so as to evenly distribute the active ingredient throughout the lactose. Pack the powder into a No. 1 empty capsule.

Tablet Containing 200 mg of 3 (2-Guanadinoethyl)- 8-0xa-3-Azabicyclo(3.2.l )Octane Hydrosulfate Monohydrate 3-( Z-Guanadinoethyl)-8-Oxa-3-Azabicyclo(3.2.l)

Octane Hydrosulfate Monohydrate 200 grams Starch 80 grams Powdered Lactose 80 grams Tale 7 H l 20 grams Weight of Granulation m sso' Tam's' Combine all ingredients, mix, and then compressinto slugs. The slugs should then be ground to form granules that will pass through a 14 to 16 mesh screen. The granules may then be recompressed into 1000 tablets using a suitable compression mold to form tablets, each weighing 380 mg.

Injectable Containing mg of 3' (o-Toluoyl )-8-Oxa3-Azabicyclo(3.2.l) Octane Per Milliliter Suitable for intramuscular, lntraperitoneal or Subcutaneous Injection 3-(o-Toluoyl)-8-0xa-3Azabicyclo(3.2.1)Octane 10.0 grams Chlorobutanol-- 310 grams Propylene Glycol 40.0 ml Water for injection. q.s. l000.0 ml

Combine the above ingredients, clarify by filtration, fill into vials, seal, and autoclave.

Having thus described my invention, 1 claim:

1. A compound represented by the formula o n-R wherein R is a radical selected from the group consisting of benzyl; phenyl; aminoalkyl (C,t0 C6); dimethylaminoalkyl (C, to C phenylacetyl; quinoxaloyl; mono-, di-, or tri-alkoxy (C, to C substituted benzoyl; phenylalkyl where the alkyl constituent thereof contains from 1 to 4 carbon atoms; alkenyl (C mono-, di-, or tri-halogen substituted phenylalkyl where the alkyl group contains from I to 4 carbon atoms and the halogen is substituted on the phenyl ring; guanadionalkyl (C, to C mono-, di-, or tri-halogen substituted benzoyl; dior tri-alkyl (C, to C substituted benzoyl; mono-, di-, or tri-halogen substituted phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms and the'haloge'n is on the phenyl ring; hexahydrobenzoyl; phenylalkenoyl wherein the alkenoyl group is a lower alkenoyl containing from 3 to 5 carbon atoms; phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms; 0- and p-alkyl (C, to C substituted phenylalkanoyl where the alkanoyl group contains 2 to 4 carbon atoms and the alkyl group is substituted on the phenyl ring; alkyl (C, to C,) substi tuted naphthylulkanoyl wherein the alkanoyl group contains ,2 to 4 carbon atoms and the alkyl group or groups are attached to the naphthyl ring; alkanoyl (C, to C,,,); haloalkyl (C, to C mono-,- di-, or trisubstituted benzoyl wherein the haloalkyl group contains from 1 to 5 halogen atoms; mono-, di-, or tr alkoxy (C, to C substituted phenylalkyl wherein the alkyl group contains l to 4 carbon atoms and the alkoxy is substituted on the phenyl ring; thienylalkylwherein R is aradical selected from the group consisting of benzyl; phenyl; phenylacetyl; quinoxaloyl; mono-, di-, or tri-alkoXy (C, to C4) substituted benzoyl; phenylalkyl where the alkyl constituent thereof contains from 1 to 4 carbon atoms; mono-, di-, or trihalogen substituted phenylalkyl where the alkyl group contains from 1 to 4 carbon atoms and the halogen is substituted on the phenyl ring; guanadinoalkyl (C, to

C mono-, di-, or tri-halogen substituted benzoyl;

mono-, di-, or tri-halogen substituted phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms and the halogen is on the phenyl ring; hexa hydrobenzoyl; phenylalkenoyl wherein the alkenoyl group is alower alkenoyl containing from3 to 5 carbon atoms; phenylalkanoyl wherein the alkanoyl group contains from 2 to 4 carbon atoms; 0- and p-alkyl 9C, to C substituted phenylalkanoyl where the alkanoyl group contains 2 to 4 carbon atoms and the alkyl group is substituted on the phenyl ring; alkyl (C, to C,) substituted naphthylalkanoyl wherein the alkanoyl group contains 2 to 4 carbon atoms and the alkyl group or groups are attached to the naphthyl ring; haloalkyl (C, to C mono-, di-, or tri-substituted benzoyl wherein the haloalkyl group contains from I to 5 halogen atoms; mono-, di-, or tri-alkoxy (C, to C substituted phenylalkyl wherein the alkyl group contains l to 4 carbon atoms and the alkoxy is substituted on the phenyl ring; thienylalkyl wherein the alkyl group contains from 1 to 4 carbon atoms; anilinocarbonyl; adamantanecarbonyl; phenylsulfonyl; monoor dicarboxyl substituted benzoyl; monoor di-hydroxyl substituted benzoyl; nicotinoyl; monoor di-alkanoyloxy (C to C,) substituted 31 benzoyl; thenoyl; phenylglyoxylyl; cycloalkyl (C to C8), and the pharmacologically acceptable acid addition salts thereof. 7

3. A compound of claim 1 wherein. R is a radical selected from the group consisting of benzyl, N- hexamethylene)-8-oxa-3-azabicyclo( 3.2. l )octane, phenyl, aminohexyl, phenylacetyl, quinoxaloyl, mmethoxybenzoyl, a-methylphenethyl, aminoethyl, propenyl, a-methyl p-chlorophenethyl, dimethylaminopropyl. phenethyl, Z-guanadinoethyl, p-chlorobenzoyl, m-

chlorobenzoyl, o-chlorobenzoyl, mchlorophenylacetyl, p-chlorophenylacetyl, N- (ethylene)-8-oxa- 3 -azabicyclo(3.2. l)octane, ,B-methylphenethyl, B, ,B-dimethylphenethyl, p-

chlorophenethyl, hexahydrobenzoyl, ochlorophenylacetyl. cinnamoyl, phenethylcarbonyl, omethylphenylacetyl, heptanoyl, m-trifluoromethylbenzoyl, p-methoxyphenethyl, a-methylthienylethyl, anilinocarbonyl, adamantanecarbonyl, phenylsulfonyl, o-carboxybenzoyl, stearoyl, o-hydroxybenzoyl, nicotinoyl, o-acetoxybenzoyl, thenoyl, phenylglyoxylyl, cyclohexyl, 3 ,4-dimethoxyphenethyl, and the pharmacologically acceptable acid-addition salts thereof.

4. a compound of claim 1 wherein R is mmethoxybenzoyl.

5. A compound of claim 1 wherein R is a-methylphenethyl.

6. A compound of claim 1 wherein R is l-propenyl.

7. A compound of claim 1 wherein R is a-methyl pchlorophenethyl.

8. A compound of claim 1 wherein R is p-, or mchlorobenzoyl.

9. A compound of claim 1 wherein R is 0-, p-, or mchlorophenylacetyl.

10. A compound of claini l wherein R is phenethylmethylphenylacetyl.

12. A compound of claim 1 wherein R is stearoyl. 13. A compound of claim 1 wherein R isphenethyl. 14. A compound of claim 1 wherein R is phenylacetyl.

15. A compound of claim 1 wherein R is aminoethyl. 16. A compound of claim 1 wherein R is thenoyl. 17.,A compound of claim 1 wherein R is nicotinoyl. 18. A compound of claim 1 wherein R is N- (ethylene)-8-oxa-3-azabicyclo(3.2. l )octane.

19. A compound of claim 1 wherein R is benzyl. 20. A compound of claim 1 wherein R is N- (hexamethylene)-8-oxa-3-azabicyclo(3.2. l )octane.

21. A compound of claim 1 wherein R isphenyl.

22. A compound of claim 1 wherein R is aminohexyl.

23. A compund of claim 1 wherein R is quinoxaloyl.

24. A compound of claim 1 wherein R is dimethylaminopropyl.

25. A compound of claim 1 wherein R is quanadinoethyl.

26. A compound ofclaim 1 wherein R is 0-, p-,or mchlorophenethyl.

27. A compound of claim 1 wherein R is hexahydrobenzoyl.

28. A compound of claim 1 wherein R is cinnamoyl.

29. A compound of claim 1 wherein R is heptanoyl.

30. A compound of claim 1 wherein R is 0-, p-. or m-trifluoromethylbenzoyl.

31. A compound of claim 1 wherein R is B,B-dimethylphenethyl. 

1. A COMPOUND REPRESENTED BY THE FORMULA
 2. A compound represented by the formula
 3. A compound of claim 1 wherein R is a radical selected from the group consisting of benzyl, N-(hexamethylene)-8-oxa-3-azabicyclo(3.2.1)octane, phenyl, aminohexyl, phenylacetyl, quinoxaloyl, m-methoxybenzoyl, Alpha -methylphenethyl, aminoethyl, propenyl, Alpha -methyl p-chlorophenethyl, dimethylaminopropyl, phenethyl, 2-guanadinoethyl, p-chlorobenzoyl, m-chlorobenzoyl, o-chlorobenzoyl, m-chlorophenylacetyl, p-chlorophenylacetyl, N-(ethylene)18-oxa-3-azabicyclo(3.2.1)octane, Beta -methylphenethyl, Beta , Beta -dimethylphenethyl, p-chlorophenethyl, hexahydrobenzoyl, o-chlorophenylacetyl, cinnamoyl, phenethylcarbonyl, o-methylphenylacetyl, heptanoyl, m-trifluoromethylbenzoyl, p-methoxyphenethyl, Alpha -methylthienylethyl, anilinocarbonyl, adamantanecarbonyl, phenylsulfonyl, o-carboxybenzoyl, stearoyl, o-hydroxybenzoyl, nicotinoyl, o-acetoxybenzoyl, thenoyl, phenylglyoxylyl, cyclohexyl, 3,4-dimethoxyphenethyl, and thepharmacologically acceptable acid addition salts thereof.
 4. a compound of claim 1 wherein R is m-methoxybenzoyl.
 5. A compound of claim 1 wherein R is Alpha -methylphenethyl.
 6. A compound of claim 1 wherein R is 1-propenyl.
 7. A compound of claim 1 wherein R is Alpha -methyl p-chlorophenethyl.
 8. A compound of claim 1 wherein R is o-, p-, or m-chlorobenzoyl.
 9. A compound of claim 1 wherein R is o-, p-, or m-chlorophenylacetyl.
 10. A compound of claim 1 wherein R is phenethylcarbonyl.
 11. A compound of claim 1 wherein R is o- or p-methylphenylacetyl.
 12. A compound of claim 1 wherein R is stearoyl.
 13. A compound of claim 1 wherein R isphenethyl.
 14. A compound of claim 1 wherein R is phenylacetyl.
 15. A compound of claim 1 wherein R is aminoethyl.
 16. A compound of claim 1 wherein R is thenoyl.
 17. A compound of claim 1 wherein R is nicotinoyl.
 18. A compound of claim 1 wherein R is N-(ethylene)-8-oxa-3-azabicyclo(3.2.1)Octane.
 19. A compound of claim 1 wherein R is benzyl.
 20. A compound of claim 1 wherein R is N-(hexamethylene)-8-oxa-3-azabicyclo(3.2.1)octane.
 21. A compound of claim 1 wherein R isphenyl.
 22. A compound of claim 1 wherein R is aminohexyl.
 23. A compund of claim 1 wherein R is quinoxaloyl.
 24. A compound of claim 1 wherein R is dimethylaminopropyl.
 25. A compound of claim 1 wherein R is quanadinoethyl.
 26. A compound of claim 1 wherein R is o-, p-, or m-chlorophenethyl.
 27. A compound of claim 1 wherein R is hexahydrobenzoyl.
 28. A compound of claim 1 wherein R is cinnamoyl.
 29. A compound of claim 1 wherein R is heptanoyl.
 30. A compound of claim 1 wherein R is o-, p-, or m-trifluoromethylbenzoyl.
 31. A compound of claim 1 wherein R is Beta , Beta -dimethylphenethyl. 